Donald G. Carlson
Eli Lilly and Company
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Featured researches published by Donald G. Carlson.
Journal of Medicinal Chemistry | 1996
Robert D. Dillard; Nicholas James Bach; Susan Elizabeth Draheim; Dennis R. Berry; Donald G. Carlson; Nickolay Y. Chirgadze; David K. Clawson; Lawrence W. Hartley; Lea M. Johnson; Noel D. Jones; Emma R. McKinney; Edward David Mihelich; Jennifer L. Olkowski; Richard Walter Schevitz; Amy C. Smith; David W. Snyder; Cynthia D. Sommers; Jean-Pierre Wery
Phospholipases (PLAs) produce rate-limiting precursors in the biosynthesis of various types of biologically active lipids involved in inflammatory processes. Increased levels of human nonpancreatic secretory phospholipase A2 (hnps-PLA2) have been detected in several pathological conditions. An inhibitor of this enzyme could have therapeutic utility. A broad screening program was carried out to identify chemical structures which could inhibit hnps-PLA2. One of the lead compounds generated by the screening program was 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (13a). We describe the syntheses, structure−activity relationships, and pharmacological activities of a series of indole-3-acetamides and related compounds derived from this lead. This SAR was undertaken with the aid of X-ray crystal structures of complexes between the inhibitors and hnps-PLA2 which were of great value in directing the SAR.
European Journal of Pharmacology | 1996
Niles Fox; Min Song; James Schrementi; John D. Sharp; Donald L. White; David W. Snyder; Lawrence W. Hartley; Donald G. Carlson; Nicholas James Bach; Robert D. Dillard; Susan Elizabeth Draheim; Jesse L. Bobbitt; Lawrence Fisher; Edward David Mihelich
Transgenic mice were created which overexpress human secretory non-pancreatic phospholipase A2 (sPLA2) pansomatically as a potential disease and drug-testing model. The mice were produced using a DNA construct in which the inducible mouse metallothionein gene promoter drives expression of a human sPLA2 minigene. High levels of sPLA2 were detected in several tissues by immunofluorescence localization. Expression in the testes caused hypospermia and male infertility. Circulating catalytically active sPLA2 could be induced to levels observed in patients undergoing a systemic inflammatory response but had no detectable effect on the mice. Therefore, these results suggest that sPLA2 hyperphospholipasemia alone may have only limited pathophysiological consequences. We further show that 3-[3-acetamide-1-benzyl-2-ethylindolyl-5-oxy]propane phosphonic acid LY311727), a potent new inhibitor of phospholipase A2 catalysis developed by our group, dramatically suppresses the circulating enzyme activity in these animals whereas 3-[3-acetamide-1-benzyl-2-propylindolyl-5-oxy]propane phosphonic acid (LY314024), a substantially less potent LY311727 analog, is without effect. These later results thus motivate the further development of this compound as a potential new therapeutic agent and valuable research tool.
Cellular Immunology | 1986
Steven H. Zuckerman; Julia Tang; Philip Marder; Larry D. Butler; Donald G. Carlson
Proteose peptone-induced peritoneal macrophages from CBA/J (H-2k) mice have been fused to a hypoxanthine phosphoribosyltransferase-negative variant of the P388D1 (H-2d) murine macrophage cell line. Six hybrid clones were isolated following HAT selection and further characterized. Five of the six clones express class I antigens of both parental haplotypes by microelisa and by flow cytometric analysis. Class II antigen expression of both haplotypes was apparent following a 72-hr incubation of the hybrids with concanavalin A-stimulated rat spleen cell supernatant. However, I-Ad was expressed in all hybrids to a greater extent than I-Ak. Three clones with the highest level of I-Ak expression, E5, C2, and C4, were capable of antigen presentation to the I-Ak-restricted T-cell line, D10.G4.1. LPS induction of the hybrids resulted in a 2- to 15-fold increase in the amount of IL-1 produced relative to the P388D1 parent. Finally, in distinction to P388D1, all hybrids demonstrated increased Fc-mediated erythrophagocytosis of chromium-labeled antibody-coated erythrocytes. These murine macrophage hybrids appear stable and should serve as useful models in understanding the regulation of macrophage function.
Journal of Leukocyte Biology | 1988
Steven H. Zuckerman; Yvonne M. Surprenant; Donald G. Carlson; Bruce Beutler
The fusion of thioglycollate‐elicited peritoneal macrophages from the lipopolysaccharide (LPS)‐nonresponsive C3H/HeJ mouse strain to a hypoxanthine phosphoribosyltransferase (HPRT)‐negative variant of the murine macrophage cell line P388D1 has resulted in the derivation of eight hybrid clones following HAT selection. Propidiumiodide staining followed by flow cytometry has demonstrated that the DNA content of the hybrids represents the sum of the parents. Codominant expression of class I antigens from both parental haplotypes is observed in the hybrids. While class II antigens are inducible following a 72‐hr induction with gamma interferon‐containing supernatants, the amount of each haplotype varies between clones. These hybrids demonstrate Fc‐mediated crythrophagocytosis in contrast to P388D1. In distinction to the C3H/HeJ primary peritoneal‐macrophage parent, LPS treatment of the hybrids results in the Increased release of both interieukin‐1 (IL‐1) and cachectin/tumor necrosis factor (TNF) into culture supernatants. Therefore, cell fusion has resulted in the stable restoration of the LPS‐responsive phenotype in C3H/HeJ macrophage hybrids. These macrophage hybrids should serve as useful models In understanding the regulation of macrophage effector functions in response to environmental stimuli.
Journal of Pharmacology and Experimental Therapeutics | 1999
David W. Snyder; Nicholas James Bach; Robert D. Dillard; Susan Elizabeth Draheim; Donald G. Carlson; Niles Fox; Neal W. Roehm; Christopher T. Armstrong; Chan H. Chang; Lawrence W. Hartley; Lea M. Johnson; Carlos R. Roman; Amy C. Smith; Min Song; Jerome H. Fleisch
Journal of Medicinal Chemistry | 1996
Robert D. Dillard; Nicholas James Bach; Susan Elizabeth Draheim; Dennis R. Berry; Donald G. Carlson; Nickolay Y. Chirgadze; David K. Clawson; Lawrence W. Hartley; Lea M. Johnson; Noel D. Jones; Emma R. McKinney; Edward David Mihelich; Jennifer L. Olkowski; Richard Walter Schevitz; Amy C. Smith; David W. Snyder; Cynthia D. Sommers; Jean-Pierre Wery
Archive | 1995
Donald G. Carlson; George Joseph Cullinan; Kennan Joseph Fahey; William T. Jackson; Neal W. Roehm; Stephen M. Spaethe
Journal of Medicinal Chemistry | 2005
J. Scott Sawyer; Douglas Wade Beight; Edward C. R. Smith; David W. Snyder; Marcia K. Chastain; Richard L. Tielking; Lawrence W. Hartley; Donald G. Carlson
Archive | 1995
Donald G. Carlson; George Joseph Cullinan; Kennan Joseph Fahey; William T. Jackson; Neal W. Roehm; Stephen M. Spaethe
Archive | 1995
Donald G. Carlson; George Joseph Cullinan; Kennan Joseph Fahey; William T. Jackson; Neal W. Roehm; Stephen M. Spaethe